US3749786A - Organic compounds in treating allergic conditions - Google Patents

Organic compounds in treating allergic conditions Download PDF

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US3749786A
US3749786A US00278244A US3749786DA US3749786A US 3749786 A US3749786 A US 3749786A US 00278244 A US00278244 A US 00278244A US 3749786D A US3749786D A US 3749786DA US 3749786 A US3749786 A US 3749786A
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formula
compounds
compound
carbon atoms
allergic conditions
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G Schwarb
J Bourquin
E Waldvogel
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Sandoz AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/78—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems condensed with rings other than six-membered or with ring systems containing such rings
    • C07D333/80—Seven-membered rings

Definitions

  • R is hydrogen, halogen or alkoxy of 1 to 4 carbon atoms, R is alkyl of 1 to 4 carbon atoms, and --AB is CH -CO or CO-CH or a pharmaceutically acceptable acid addition salt thereof.
  • the present invention provides a method of treating allergic conditions, which comprises administering a therapeutically effective dose of a histaminolytic of Formula I,
  • R is hydrogen, halogen, or alkoxy of 1 to 4 carbon atoms
  • R is alkyl of l to 4 carbon atoms
  • --AB is the group --CH CO- or -CO-CH or a pharmaceutically acceptable acid addition salt thereof.
  • Histamine toxicity test male and female guinea pigs having a weight of 200 to 500 g. are utilized as test animals. The compound to be tested is administered subcutaneously to the animals at various dosage levels. Three hours later 20 mg./kg. of histamine dihydrochloride are administered subcutaneously. In the event of the guinea pigs surviving 12 hours after the application of the histamine, they are considered as being protected. The results obtained at the various dosage levels are transferred onto paper and the ED value is ascertained in the usual manner.
  • Acetylchloline toxicity test male and female guinea pigs having a weight of 200 to 500 g. are utilized as test animals. The compound to be tested is administered subcutaneously to the animals at various dosage levels. 30 minutes later 160 mg./kg. of acetylcholine chloride are administered subcutaneously. In the event of the guinea pigs surviving 12 hours after the application of the acetylchloline, they are considered as being protected. The results obtained at the various dosage levels are transferred onto graph paper and the ED value is ascertained in the usual manner.
  • Serotonin toxicity test male guinea pigs having a weight of 200 to 500 g. are utilized as test animals. The compound to be tested is administered subcutaneously to the animals at various dosage levels. Three hours later mg./kg. of serotonin creatinine sulfate are administered intravenously (via the penis vein). In the event of the guinea pigs surviving 12 hours after the application of the serotonin, they are considered as being protected. The results obtained at the various dosage levels are transferred onto graph paper and the ED value is ascertained in the usual manner.
  • antaminics are useful antaminics, i.e. they are useful in antagonizing the effects of each of the biogenic amines histamine, serotonin and acetylcholine, as indicated by the above mentioned toxicity tests in guinea pigs.
  • the dose of the histaminolytic compound to be administered in the method will naturally vary depending on the compound employed, the mode of administration and the treatment desired. However, the doses are similar for compounds of Formula Ia and compounds of Formula Ib,
  • the daily dose is from about 0.25 to about 10 milligrams of the compound, which may be administered in divided doses 2 to 3 times a day or in sustained release form.
  • Unit dosage forms suitable for oral administration incorporate from about 0.1 to about milligrams of the compound, in association with a pharmaceutical carrier or diluent.
  • the compounds of Formula I may be administered in pharmaceutically acceptable acid addition salt form.
  • Such salts possess the same order of activity as the free bases and are readily prepared in conventional manner.
  • Suitable such salt forms include mineral acid salts such as the hydrochloride, hydrobromide and sulphate, and organic acid salts such as the fumarate, maleate, tartrate, methane-, ethaneand benzene-sulphonate, citrate and malate.
  • a compound of Formula I is obtained by a process comprising:
  • R and R are as defined above, and X is in the 9 or position and is an OR radical, wherein R is alkyl of 1 to 4 carbon atoms, a radical of Formula III,
  • R is hydrogen or alkyl of 1 to 4 carbon atoms which is unbranched on the a carbon atom, or
  • R and R together with the nitrogen atom, form a saturated 5- or 6-membered heterocyclic ring, the heterocycle being selected from the group of heterocycles containing 1 or 2 nitrogen atoms, 1 nitrogen atom and a further hetero atom selected from oxygen and sulphur, and 1 nitrogen atom and one nitrogen atom substituted by an alkyl radical of 1 to 4 carbon atoms, (b) Alkylating a compound of Formula IV,
  • the resulting compound of Formula I may be isolated in the form of a free base or as an acid addition salt thereof.
  • R radicals are hydrogen, chlorine, bromine and methoxy.
  • X in Formula II is suitably the tert.butoxy group, the dimethylamino, diethylamino or n-butylamino radical, and when X denotes a heterocycle, it may be, e.g., the piperidine, piperazino, morpholino, pyrrolidino or N- methyl-piperazino radical.
  • inert solvent signifies an organic solvent which is inert under the reaction conditions.
  • the production of compounds of Formula I in accordance with process variant (a) may, for example, be effected by heating compounds of Formula II in an aqueous acid solution.
  • the reaction temperature is not critical.
  • a suitable reaction temperature is approximately 50 to C.; the reaction is preferably eifected at the reflux temperature of the reaction mixture.
  • Suitable acids are aqueous inorganic acids, e.g. hydrochloric, sulphuric or phosphoric acid, and aqueous organic acids, e.g. formic, acetic, fumaric or oxalic acid.
  • the hydrolysis may also be carried out by hydrolyzing a mixture of compounds of Formula II substituted in the 9 position with corresponding compounds of Formula II substituted in the 10 position.
  • Such hydrolysis results in a mixture of isomers of Ia and Ib, as shown above, and said isomers may be separated in conventional manner, for example by fractional crystallization of a salt, e.g., a fumarate, to give the desired isomer.
  • Alkylation of the compounds of Formula IV in accordance with process variant (b) may be efiected in accordance with known methods, e.g. by treatment with alkyl halides, with esters of organic sulphonic acids, e.g. methane-, benzeneor p-toluene-sulphonic acid, or with dialkyl sulphates, in an inert solvent and in the presence of a basic condensation agent.
  • organic sulphonic acids e.g. methane-, benzeneor p-toluene-sulphonic acid
  • dialkyl sulphates e.g. methane-, benzeneor p-toluene-sulphonic acid
  • the compounds of Formula I may be isolated from the worked up reaction mixture in conventional manner, e.g. chromatographically.
  • the compounds of Formula II are likewise new.
  • R and R are as defined above, and X is in the 9 or 10 position and is a radical of Formula III,
  • R and R are as defined above, and
  • Y is chlorine or bromine in the 9 or position, or a mixture of a compound of Formula V substituted in the 9 position, with a compound of Formula V substituted in the 10 position, in the presence of an acid-binding agent, e.g. an alkali metal amide or hydride or a potassium alcoholate, e.g. a potassium tert.butylate, with the corresponding amine or saturated, nitrogen-containing heterocycle.
  • an acid-binding agent e.g. an alkali metal amide or hydride or a potassium alcoholate, e.g. a potassium tert.butylate
  • This reaction yields a mixture of compounds of Formula Ila substituted in the 9 position, with compounds of Formula IIa substituted in the 10 position.
  • a separation may be effected in accordance with known methods, but is not necessary; the worked up mixture is generally further worked up as such.
  • (IIb) may be produced by reacting compounds of Formula V with a potassium alcoholate, preferably an excess of the same, if desired in an inert organic solvent, e.g. a cyclic or open chain ether such as dioxane.
  • a potassium alcoholate preferably an excess of the same, if desired in an inert organic solvent, e.g. a cyclic or open chain ether such as dioxane.
  • the reaction is preferably effected at room temperature or at a slightly elevated temperature.
  • This reaction likewise yields a mixture of the compounds of Formula IIb substituted in the 9 position, with the compounds of Formula IIb substituted in the 10 position, which mixture is generally not separated, but further worked up after working up the reaction mixture.
  • the compounds of Formula IV may, for example, be obtained by dealkylation of compounds of Formula la in accordance with known methods.
  • compounds of Formula Ia are treated with a cyanogen halide, preferably cyanogen bromide, or a halogen formic acid ester.
  • the radical R is first replaced by the cyano or alkoxycarbonyl group.
  • the reaction is conveniently effected in an inert organic solvent, e.g. an open chain or cyclic ether such as diethyl ether or tetrahydrofuran, an aromatic hydrocarbon such as benzene, a chlorinated aliphatic hydrocarbon such as methylene chloride, and at a reaction temperature between room temperature and the boiling temperature of the reaction mixture.
  • the cyano or alkoxy-carbonyl group is subsequently split off in accordance with known methods, e.g. by acid hydrolysis.
  • R R and Y are as defined above.
  • the removal of water may, for example, be elfected with a mineral acid such as hydrochloric acid in ethanol, or with a strong organic acid, acetic anhydride or an inorganic acid halide as water-removing agent.
  • a mineral acid such as hydrochloric acid in ethanol
  • a strong organic acid such as acetic anhydride or an inorganic acid halide
  • the reaction is preferably efiected with hydrobromic acid in an inert organic solvent, e.g. a lower alcohol.
  • Compounds of Formula VI may, for example, be produced by adding dropwise a solution of a compound of wherein R and Y are as defined above,
  • an inert organic solvent e.-g. an open chain or cyclic ether such as tetrahydrofuran or diethyl ether, to a magnesium organic halogen compound of Formula VIII,
  • R -N Mg-Hal wherein R is as defined above, and Hal signifies chlorine
  • the compounds of Formula VII are likewise new and may, for example, be produced by chlorinating or brominating a compound of Formula IX,
  • R is hydrogen, halogen or alkoxy of 1 to 4 carbon atoms, R; is alkyl of l to 4 carbon atoms, and A--B- is -CH CO- or C0CH or a pharmaceutically acceptable acid addition salt thereof.
  • R and R are as defined in claim 1, or a pharmaceutically acceptable acid addition salt thereof.
  • histaminolytic is 4-(1-methyl-4-piperidylidene)-4H-benz0 [4,5]cyclohepta[1,2 b]thiophen 10(9H) one or a pharmaceutically acceptable acid addition salt thereof.

Abstract

THE PRESENT INVENTION CONCERNS A NOVEL METHOD OF TREATING ALLERGIC CONDITIONS, WHICH COMPRISES ADMINISTERING AN EFFECTIVE DOSE OF A HISTAMINOLYTIC OF THE FORMULA

A<(-(R1-1,2-PHENYLENE)-C(=C<(-(CH2)2-N(-R2)-(CH2)2-))-

(3,2-THIOPHENYLENE)-B-)

WHEREIN R1 IS HYDROGEN, HALOGEN OR ALKOXY OF 1 TO 4 CARBON ATOMS, R2 IS ALKYL OF 1 TO 4 CARBON ATOMS, AND -A-B- IS -CH2-CO- OR -CO-CH2, OR A PHARMACEUTICALLY ACCEPTABLE ACID ADDITON SALT THEREOF.

Description

United States Patent U.S. Cl. 424-267 7 Claims ABSTRACT OF THE DISCLOSURE The present invention concerns a novel method of treating allergic conditions, which comprises administering an elfective dose of a histaminolytic of the formula:
Ill
wherein R is hydrogen, halogen or alkoxy of 1 to 4 carbon atoms, R is alkyl of 1 to 4 carbon atoms, and --AB is CH -CO or CO-CH or a pharmaceutically acceptable acid addition salt thereof.
This application is a continuation in part of copending application No. 120,738, filed Mar. 3, 1971, now U.S. 3,682,930 issued Aug. 8, 1972. The invention relates to a novel method of treating allergic conditions.
The present invention provides a method of treating allergic conditions, which comprises administering a therapeutically effective dose of a histaminolytic of Formula I,
wherein R is hydrogen, halogen, or alkoxy of 1 to 4 carbon atoms, R is alkyl of l to 4 carbon atoms, and --AB is the group --CH CO- or -CO-CH or a pharmaceutically acceptable acid addition salt thereof.
The compounds were tested in guinea pigs in the following tests:
Histamine toxicity test: male and female guinea pigs having a weight of 200 to 500 g. are utilized as test animals. The compound to be tested is administered subcutaneously to the animals at various dosage levels. Three hours later 20 mg./kg. of histamine dihydrochloride are administered subcutaneously. In the event of the guinea pigs surviving 12 hours after the application of the histamine, they are considered as being protected. The results obtained at the various dosage levels are transferred onto paper and the ED value is ascertained in the usual manner.
3,749,786 Patented July 31, 1973 ice Acetylchloline toxicity test: male and female guinea pigs having a weight of 200 to 500 g. are utilized as test animals. The compound to be tested is administered subcutaneously to the animals at various dosage levels. 30 minutes later 160 mg./kg. of acetylcholine chloride are administered subcutaneously. In the event of the guinea pigs surviving 12 hours after the application of the acetylchloline, they are considered as being protected. The results obtained at the various dosage levels are transferred onto graph paper and the ED value is ascertained in the usual manner.
Serotonin toxicity test: male guinea pigs having a weight of 200 to 500 g. are utilized as test animals. The compound to be tested is administered subcutaneously to the animals at various dosage levels. Three hours later mg./kg. of serotonin creatinine sulfate are administered intravenously (via the penis vein). In the event of the guinea pigs surviving 12 hours after the application of the serotonin, they are considered as being protected. The results obtained at the various dosage levels are transferred onto graph paper and the ED value is ascertained in the usual manner.
From the above tests it was shown that compounds of Formula Ia.
2 (Ia) wherein R and R are as defined above.
are useful as specific histaminolytics, as indicated by their wherein R and R are as defined above,
are useful antaminics, i.e. they are useful in antagonizing the effects of each of the biogenic amines histamine, serotonin and acetylcholine, as indicated by the above mentioned toxicity tests in guinea pigs.
The dose of the histaminolytic compound to be administered in the method will naturally vary depending on the compound employed, the mode of administration and the treatment desired. However, the doses are similar for compounds of Formula Ia and compounds of Formula Ib,
and satisfactory results for each group of compounds are obtained at doses between abut 0.004 mg./kg. and 0.15 mg./ kg. animal body weight. For the larger mammals, the daily dose is from about 0.25 to about 10 milligrams of the compound, which may be administered in divided doses 2 to 3 times a day or in sustained release form. Unit dosage forms suitable for oral administration incorporate from about 0.1 to about milligrams of the compound, in association with a pharmaceutical carrier or diluent.
The compounds of Formula I may be administered in pharmaceutically acceptable acid addition salt form. Such salts possess the same order of activity as the free bases and are readily prepared in conventional manner. Suitable such salt forms include mineral acid salts such as the hydrochloride, hydrobromide and sulphate, and organic acid salts such as the fumarate, maleate, tartrate, methane-, ethaneand benzene-sulphonate, citrate and malate.
A compound of Formula I is obtained by a process comprising:
(a) Hydrolyzing a compound of Formula II,
wherein R and R are as defined above, and X is in the 9 or position and is an OR radical, wherein R is alkyl of 1 to 4 carbon atoms, a radical of Formula III,
CHgRa R4 (III) wherein R is hydrogen or alkyl of 1 to 4 carbon atoms, and
R is hydrogen or alkyl of 1 to 4 carbon atoms which is unbranched on the a carbon atom, or
R and R together with the nitrogen atom, form a saturated 5- or 6-membered heterocyclic ring, the heterocycle being selected from the group of heterocycles containing 1 or 2 nitrogen atoms, 1 nitrogen atom and a further hetero atom selected from oxygen and sulphur, and 1 nitrogen atom and one nitrogen atom substituted by an alkyl radical of 1 to 4 carbon atoms, (b) Alkylating a compound of Formula IV,
wherein R is as defined above,
wherein R and R are as defined above.
The resulting compound of Formula I may be isolated in the form of a free base or as an acid addition salt thereof.
Particularly suitable R radicals are hydrogen, chlorine, bromine and methoxy.
The symbol X in Formula II is suitably the tert.butoxy group, the dimethylamino, diethylamino or n-butylamino radical, and when X denotes a heterocycle, it may be, e.g., the piperidine, piperazino, morpholino, pyrrolidino or N- methyl-piperazino radical.
The term inert solvent as used herein signifies an organic solvent which is inert under the reaction conditions.
The production of compounds of Formula I in accordance with process variant (a) may, for example, be effected by heating compounds of Formula II in an aqueous acid solution. The reaction temperature is not critical. A suitable reaction temperature is approximately 50 to C.; the reaction is preferably eifected at the reflux temperature of the reaction mixture.
Suitable acids are aqueous inorganic acids, e.g. hydrochloric, sulphuric or phosphoric acid, and aqueous organic acids, e.g. formic, acetic, fumaric or oxalic acid.
The hydrolysis may also be carried out by hydrolyzing a mixture of compounds of Formula II substituted in the 9 position with corresponding compounds of Formula II substituted in the 10 position. Such hydrolysis results in a mixture of isomers of Ia and Ib, as shown above, and said isomers may be separated in conventional manner, for example by fractional crystallization of a salt, e.g., a fumarate, to give the desired isomer.
Alkylation of the compounds of Formula IV in accordance with process variant (b) may be efiected in accordance with known methods, e.g. by treatment with alkyl halides, with esters of organic sulphonic acids, e.g. methane-, benzeneor p-toluene-sulphonic acid, or with dialkyl sulphates, in an inert solvent and in the presence of a basic condensation agent.
The compounds of Formula I may be isolated from the worked up reaction mixture in conventional manner, e.g. chromatographically.
The compounds of Formula II are likewise new.
Compounds of Formula IIa,
wherein R and R are as defined above, and X is in the 9 or 10 position and is a radical of Formula III,
may, for example, be obtained by reacting a compound of Formula V,
wherein R and R are as defined above, and
Y is chlorine or bromine in the 9 or position, or a mixture of a compound of Formula V substituted in the 9 position, with a compound of Formula V substituted in the 10 position, in the presence of an acid-binding agent, e.g. an alkali metal amide or hydride or a potassium alcoholate, e.g. a potassium tert.butylate, with the corresponding amine or saturated, nitrogen-containing heterocycle. 7
This reaction yields a mixture of compounds of Formula Ila substituted in the 9 position, with compounds of Formula IIa substituted in the 10 position. A separation may be effected in accordance with known methods, but is not necessary; the worked up mixture is generally further worked up as such.
Compounds of Formula IIb,
(IIb) may be produced by reacting compounds of Formula V with a potassium alcoholate, preferably an excess of the same, if desired in an inert organic solvent, e.g. a cyclic or open chain ether such as dioxane. The reaction is preferably effected at room temperature or at a slightly elevated temperature.
This reaction likewise yields a mixture of the compounds of Formula IIb substituted in the 9 position, with the compounds of Formula IIb substituted in the 10 position, which mixture is generally not separated, but further worked up after working up the reaction mixture.
The compounds of Formula IV may, for example, be obtained by dealkylation of compounds of Formula la in accordance with known methods. For example, compounds of Formula Ia are treated with a cyanogen halide, preferably cyanogen bromide, or a halogen formic acid ester. In this reaction the radical R is first replaced by the cyano or alkoxycarbonyl group. The reaction is conveniently effected in an inert organic solvent, e.g. an open chain or cyclic ether such as diethyl ether or tetrahydrofuran, an aromatic hydrocarbon such as benzene, a chlorinated aliphatic hydrocarbon such as methylene chloride, and at a reaction temperature between room temperature and the boiling temperature of the reaction mixture. The cyano or alkoxy-carbonyl group is subsequently split off in accordance with known methods, e.g. by acid hydrolysis.
The compounds of Formula V. which are likewise new,
may be obtained by dehydrating a compound of Formula VI,
wherein R R and Y are as defined above.
The removal of water, may, for example, be elfected with a mineral acid such as hydrochloric acid in ethanol, or with a strong organic acid, acetic anhydride or an inorganic acid halide as water-removing agent. However, the reaction is preferably efiected with hydrobromic acid in an inert organic solvent, e.g. a lower alcohol.
Compounds of Formula VI may, for example, be produced by adding dropwise a solution of a compound of wherein R and Y are as defined above,
in an inert organic solvent, e.-g. an open chain or cyclic ether such as tetrahydrofuran or diethyl ether, to a magnesium organic halogen compound of Formula VIII,
R -N Mg-Hal wherein R is as defined above, and Hal signifies chlorine,
bromine or iodine,
(VIII) in the same inert solvent in which it was prepared, conveniently stirring the reaction mixture for about 1 /2 hours, preferably at room temperature, and subsequently hydrolyzing. Hydrolysis may, for example, be efiected with an aqueous ammonium chloride solution in the cold.
The compounds of Formula VII are likewise new and may, for example, be produced by chlorinating or brominating a compound of Formula IX,
wherein R is as defined above,
to obtain the corresponding 9,10-dichloroor 9,10- dibromo compounds, and subsequently converting the resulting compounds into compounds of Formula VII under alkaline conditions, e.g. by reaction with a solution of potassium hydroxide in an inert organic solvent such as methanol, or, e.g., by heating with a commercial solution or sodium or potassium hydroxide in the presence of a lower alcohol solvent.
all
wherein R is as defined above,
wherein R is hydrogen, halogen or alkoxy of 1 to 4 carbon atoms, R; is alkyl of l to 4 carbon atoms, and A--B- is -CH CO- or C0CH or a pharmaceutically acceptable acid addition salt thereof.
2. A method of treating allergic conditions according to claim 1, wherein the histaminolytic is of the formula:
wherein R and R are as defined in claim 1, or a pharmaceutically acceptable acid addition salt thereof.
3. A method according to claim 1, in which the histaminolytic is administered in an amount of 0.004 to 0.15 mg./kg. animal body weight.
4. A method according to claim 2, in which the histaminolytic is administered in an amount of 0.004 to 0.15 mg./kg. animal body weight.
5. A method according to claim 4, in which the histaminolytic is 4-(1-methyl-4-piperidylidene)-4I-I-benzo [4,5]cyclohepta[1,2-b]thiophen-10(9H)-one or a pharmaceutically acceptable acid addition salt thereof.
6. A method according to claim 3, in which the histaminolytic compound is administered in an amount of 0.25 to 10 mg. per day.
7. A method according to claim 2, in which the histaminolytic is 4-(1-methyl-4-piperidylidene)-4H-benz0 [4,5]cyclohepta[1,2 b]thiophen 10(9H) one or a pharmaceutically acceptable acid addition salt thereof.
References Cited UNITED STATES PATENTS STANLEY J. FRIEDMAN, Primary Examiner I I UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3 r 9 r786 Dated uly 31 1973 Inventor(s) Jean-Pierre Bourquin, Gustab Schwarb, Erwin Waldvogel It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:
Column 8 claim 2 lines 5 to 15 the structure should appear as follows.
Signed and sealed this 11th day of June 19714..
(SEAL) Attest: Y
EDWARD M.FLE'1CI-IER, JR. 0 MARSHKLL 1mm Attesting Officer Commissioner ofPatents R P0405) (0459) v USCOMM-DC 60376-P59 9 U. 5 GOVERNMENT PBIPQ'H'IG OFFICE l9" O-lII-Jl,
US00278244A 1970-03-11 1972-08-07 Organic compounds in treating allergic conditions Expired - Lifetime US3749786A (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CH359870A CH533639A (en) 1970-03-11 1970-03-11 Benzo cyclo hepta-thiophenes
CH1159370A CH531000A (en) 1970-03-11 1970-07-31 Process for the preparation of new benzocycloheptathiophenes
CH1412070A CH537404A (en) 1970-09-24 1970-09-24 Benzocyclo heptathiophene prodn - esp 4-(amino alkylidene) -4h- benzo (4,5) cyclohepta(1,2-b) thiophene-10 (9h) - ones from the
CH163271 1971-02-04

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US120738A Expired - Lifetime US3682930A (en) 1970-03-11 1971-03-03 4(1-alkyl-4-piperidylidine)-4h-benzo {84,5{9 {0 cyclohepta {8 1,2{14 6{9
US00178449A Expired - Lifetime US3770728A (en) 1970-03-11 1971-09-07 Substituted 4h-benzo(4,5)cyclohepta(1,2-b)thiophen-10(9h)-ones
US00278244A Expired - Lifetime US3749786A (en) 1970-03-11 1972-08-07 Organic compounds in treating allergic conditions
US00278738A Expired - Lifetime US3853915A (en) 1970-03-11 1972-08-08 9-or 10-halo-4h-benzo{8 4,5{9 cyclo-hepta{8 1,2-b{9 thiophen-4-ones

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US120738A Expired - Lifetime US3682930A (en) 1970-03-11 1971-03-03 4(1-alkyl-4-piperidylidine)-4h-benzo {84,5{9 {0 cyclohepta {8 1,2{14 6{9
US00178449A Expired - Lifetime US3770728A (en) 1970-03-11 1971-09-07 Substituted 4h-benzo(4,5)cyclohepta(1,2-b)thiophen-10(9h)-ones

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US00278738A Expired - Lifetime US3853915A (en) 1970-03-11 1972-08-08 9-or 10-halo-4h-benzo{8 4,5{9 cyclo-hepta{8 1,2-b{9 thiophen-4-ones

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DE (2) DE2111071C3 (en)
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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3853915A (en) * 1970-03-11 1974-12-10 Sandoz Ltd 9-or 10-halo-4h-benzo{8 4,5{9 cyclo-hepta{8 1,2-b{9 thiophen-4-ones
US5075322A (en) * 1989-11-22 1991-12-24 Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) Selenophen derivatives, a preparation process of the same and therapeutical compositions containing them
US5089496A (en) * 1986-10-31 1992-02-18 Schering Corporation Benzo[5,6]cycloheptapyridine compounds, compositions and method of treating allergies
US5438062A (en) * 1986-10-31 1995-08-01 Schering Corporation Benzo(5,6)cycloheptapyridines, compositions and methods of use
AT400521B (en) * 1986-06-21 1996-01-25 Sandoz Ag METHOD FOR PRODUCING A SOLID ORAL PHARMACEUTICAL KETOTIFIC COMPOSITION
WO1998056381A1 (en) * 1997-06-09 1998-12-17 Bridge Pharma, Inc. Compounds with combined antihistaminic and mast cell stabilizing activities, intended for ophthalmic use
US5891460A (en) * 1995-06-07 1999-04-06 University Of Southern California University Park Campus Method for reducing or preventing post-surgical adhesion formation using ketotifen and analogs thereof
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RU2483063C2 (en) * 2008-08-01 2013-05-27 Ниппон Дзоки Фармасьютикал Ко., Лтд. Aminopropylidene derivatives

Families Citing this family (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3960894A (en) * 1972-01-24 1976-06-01 Sandoz Ltd. 9-Bromo-or chloro-9,10-dihydro-10-dihydro-10-alkoxy-4H-benzo[4,5]cyclo-hepta[1,2-b]thiophen-4-ones
BE794377A (en) * 1972-01-24 1973-07-23 Sandoz Sa NEW DERIVATIVES OF BENZO-CYCLOHEPTA-THIOPHENE
US4072756A (en) * 1973-05-17 1978-02-07 Sandoz Ltd. Tricyclo piperidino ketones and soporific compositions thereof
CA1041100A (en) * 1973-10-04 1978-10-24 Herbert G. Johnson Pyridine-diyldioxamic acid and derivatives
CH580621A5 (en) * 1973-10-08 1976-10-15 Sandoz Ag
US4073915A (en) * 1975-05-20 1978-02-14 Sandoz Ltd. Treating asthma
FI761607A (en) * 1975-06-16 1976-12-17 Sandoz Ag
US4128549A (en) * 1976-02-27 1978-12-05 Sandoz Ltd. Precursors of 4-(1-alkyl-4-piperidylidene-4H-benzo[4,5]cyclohepta-[1,2-b]thiophen-10(9H)-ones
US4282233B1 (en) * 1980-06-19 2000-09-05 Schering Corp Antihistaminic 11-(4-piperidylidene)-5h-benzoÄ5,6Ü-cyclohepta-Ä1,2Ü-pyridines
DE3045135A1 (en) * 1980-11-29 1982-06-09 Sandoz-Patent-GmbH, 7850 Lörrach BODEGRADABLE POLYMERS CONTAINING PHARMACEUTICAL COMPOSITIONS
CA2038417A1 (en) * 1990-04-11 1991-10-12 Yasuo Ito Piperidine compounds, method for preparation thereof, and a pharmaceutical composition comprising the same
WO1992006981A1 (en) * 1990-10-10 1992-04-30 Schering Corporation Substituted imidazobenzazepines and imidazopyridoazepines
US6221897B1 (en) * 1998-06-10 2001-04-24 Aventis Pharma Deutschland Gmbh Benzothiepine 1,1-dioxide derivatives, a process for their preparation, pharmaceuticals comprising these compounds, and their use
HUP0202671A3 (en) * 1999-09-13 2005-01-28 Bridge Pharma Inc Sarasota Optically active isomers of ketotifen and therapeutically active metabolites thereof
WO2001039774A1 (en) * 1999-12-01 2001-06-07 Klein Pharmaceuticals Topical administration of ketotifen
US20030212078A1 (en) * 2001-05-17 2003-11-13 Klein Gerald L. Topical administration of pharmacological compositions for non-systemic treatment of pruritus
DE602004014470D1 (en) * 2003-01-14 2008-07-31 Gilead Sciences Inc COMPOSITIONS AND METHODS FOR ANTIVIRAL COMBINATION THERAPY
CN100381439C (en) * 2005-04-05 2008-04-16 浙江华海药业股份有限公司 Prepn process of 9,10-dibromo-9,10-dihydro-4H-benzo-[4,5]-suberene-[1,2-b]-thienyl-4-one
TWI375560B (en) 2005-06-13 2012-11-01 Gilead Sciences Inc Composition comprising dry granulated emtricitabine and tenofovir df and method for making the same
TWI471145B (en) 2005-06-13 2015-02-01 Bristol Myers Squibb & Gilead Sciences Llc Unitary pharmaceutical dosage form
WO2008153761A1 (en) * 2007-05-23 2008-12-18 Mastcell Pharmaceuticals, Inc. Methods
WO2009142772A2 (en) 2008-05-23 2009-11-26 Mastcell Pharmaceuticals, Inc. Methods and treatment for allergies and inflammation associated with gastrointestinal diseases
JP5606440B2 (en) * 2009-07-28 2014-10-15 日本臓器製薬株式会社 Method for producing thiabenzoazulene propionic acid derivatives
KR102051030B1 (en) 2011-10-28 2019-12-02 루메나 파마수티컬즈, 인코포레이티드 Bile acid recycling inhibitors for treatment of pediatric cholestatic liver diseases
US8557846B1 (en) 2012-10-23 2013-10-15 Bridge Pharma, Inc. Medicinal treatment of dermal diseases in dogs
US8778971B2 (en) 2012-10-23 2014-07-15 Bridge Pharma, Inc. Medicinal treatment of dermal diseases in companion animals
US20140120121A1 (en) 2012-10-30 2014-05-01 Bridge Pharma, Inc. Medicinal treatment of atopic inflammatory diseases
US20150272941A1 (en) 2012-10-30 2015-10-01 Bridge Pharma, Inc. Medicinal treatment of chronic pulmonary inflammatory diseases with norketotifen
US9345697B2 (en) 2013-08-06 2016-05-24 Bridge Pharma, Inc. Methods of treatment of non-histaminic pruritus
US9439895B2 (en) 2013-08-06 2016-09-13 Bridge Pharma, Inc. Methods of treating pruritic conditions mediated through non-histaminergic mechanisms in diabetic patients
US9138431B2 (en) 2013-08-06 2015-09-22 Bridge Pharma, Inc. Methods of treatment of histamine H-4 receptor-related pruritus
EP3307270B1 (en) 2015-06-11 2018-10-17 Bridge Pharma, Inc. Methods of treatment of non-histaminic pruritus in mammals
MX2018011699A (en) 2018-09-26 2019-07-24 Federico Amezcua Amezcua A synergistic pharmaceutical composition of leukotriene receptor antagonist and a histamine h1 inverse agonist.
US10959992B2 (en) 2019-02-22 2021-03-30 Bridge Pharma Inc. Methods of treatment of asthma and COPD

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE636717A (en) * 1962-08-31
FR1437412A (en) * 1963-12-19 1966-05-06 Sandoz Sa New benzo-cyclohepta-thiophenes and their preparation
US3491103A (en) * 1963-12-19 1970-01-20 Sandoz Ag Certain 4h-benzo(4,5)cyclohepta-(1,2-b) thiophenes
GB1084450A (en) * 1963-12-20 1967-09-20 Sandoz Ltd Improvements in or relating to 4h-benzo[4,5]cyclohepta-[1,2-b] thiophene derivatives
CH537897A (en) * 1968-03-20 1973-06-15 Hoffmann La Roche Process for the preparation of tricyclic compounds
US3574199A (en) * 1968-06-28 1971-04-06 Searle & Co 6-(aminoalkyl- and aminoalkylidene)-1,1a,6,10b -tetrahydro-dibenzo(a,e)cyclopropa(c)cycloheptenes
CH531000A (en) * 1970-03-11 1972-11-30 Sandoz Ag Process for the preparation of new benzocycloheptathiophenes
US3709947A (en) * 1971-07-26 1973-01-09 Searle & Co 6-chloropropylidene-1,1a,6,10b-tetrahydrobenzo(a,e)cyclopropa(c)cycloheptenes

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3853915A (en) * 1970-03-11 1974-12-10 Sandoz Ltd 9-or 10-halo-4h-benzo{8 4,5{9 cyclo-hepta{8 1,2-b{9 thiophen-4-ones
AT400521B (en) * 1986-06-21 1996-01-25 Sandoz Ag METHOD FOR PRODUCING A SOLID ORAL PHARMACEUTICAL KETOTIFIC COMPOSITION
US5089496A (en) * 1986-10-31 1992-02-18 Schering Corporation Benzo[5,6]cycloheptapyridine compounds, compositions and method of treating allergies
US5438062A (en) * 1986-10-31 1995-08-01 Schering Corporation Benzo(5,6)cycloheptapyridines, compositions and methods of use
US5151423A (en) * 1989-05-01 1992-09-29 Schering Corporation Heterocyclic n-oxide derivatives of substituted benzo[5,6]cycloheptapyridines, compositions and methods of use
US5075322A (en) * 1989-11-22 1991-12-24 Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) Selenophen derivatives, a preparation process of the same and therapeutical compositions containing them
AT398570B (en) * 1989-11-22 1994-12-27 Sod Conseils Rech Applic NEW SELENOPHENE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR THERAPEUTIC COMPOSITIONS
US5891460A (en) * 1995-06-07 1999-04-06 University Of Southern California University Park Campus Method for reducing or preventing post-surgical adhesion formation using ketotifen and analogs thereof
WO1998056381A1 (en) * 1997-06-09 1998-12-17 Bridge Pharma, Inc. Compounds with combined antihistaminic and mast cell stabilizing activities, intended for ophthalmic use
US6207684B1 (en) 1997-06-09 2001-03-27 Bridge Pharma, Inc. Compounds with combined antihistaminic and mast cell stabilizing activities, intended for ophthalmic use
US8377967B2 (en) 2008-01-30 2013-02-19 Nippon Zoki Pharmaceutical Co., Ltd. Piperidine derivative
RU2483063C2 (en) * 2008-08-01 2013-05-27 Ниппон Дзоки Фармасьютикал Ко., Лтд. Aminopropylidene derivatives

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CA947767A (en) 1974-05-21
GB1360219A (en) 1974-07-17
NL167431C (en) 1981-12-16
DE2111071B2 (en) 1978-11-09
FR2107917A1 (en) 1972-05-12
DE2111071C3 (en) 1979-07-12
OA03786A (en) 1971-12-24
DE2111071A1 (en) 1971-09-23
AT319238B (en) 1974-12-10
US3853915A (en) 1974-12-10
FR2085695B1 (en) 1974-11-15
NL171449C (en) 1983-04-05
GB1355537A (en) 1974-06-05
GB1355538A (en) 1974-06-05
US3682930A (en) 1972-08-08
BE764019A (en) 1971-09-09
CA960673A (en) 1975-01-07
SE368954B (en) 1974-07-29
DE2144490A1 (en) 1972-03-30
NL7111808A (en) 1972-03-28
BE771964A (en) 1972-02-29
FR2107917B1 (en) 1975-04-18
GB1355539A (en) 1974-06-05
AT321905B (en) 1975-04-25
CH531000A (en) 1972-11-30
LU63829A1 (en) 1972-06-27
NL7103174A (en) 1971-09-14
LU62757A1 (en) 1971-10-13
OA03692A (en) 1971-12-24
US3770728A (en) 1973-11-06
FR2085695A1 (en) 1971-12-31
SE378820B (en) 1975-09-15

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